Digital Commons Network^™

Large Language Models As Information Providers For Appropriate Antimicrobial Use: Computational Text Analysis And Expert-Rated Comparison Of Chatgpt, Claude And Gemini, Marcello Di Pumpo, Maria Rosaria Gualano, Danilo Buonsenso, Francesca Raffaelli, Daniele Donà, Vittorio Maio, Patrizia Laurenti, Walter Ricciardi, Leonardo Villani

College of Population Health Faculty Papers

OBJECTIVES: Antimicrobial resistance is a critical public health threat. Large language models (LLMs) show great capability for providing health information. This study evaluates the effectiveness of LLMs in providing information on antibiotic use and infection management.

METHODS: Using a mixed-method approach, responses to healthcare expert-designed scenarios from ChatGPT 3.5, ChatGPT 4.0, Claude 2.0 and Gemini 1.0, in both Italian and English, were analysed. Computational text analysis assessed readability, lexical diversity and sentiment, while content quality was assessed by three experts via DISCERN tool.

RESULTS: 16 scenarios were developed. A total of 101 outputs and 5454 Likert-scale (1-5) scores were obtained …

Stereoelectroencephalography Reveals Neural Signatures Of Multisensory Integration In The Human Superior Temporal Sulcus During Audiovisual Speech Perception, Yue Zhang, John F Magnotti, Xiang Zhang, Zhengjia Wang, Yingjia Yu, Kathryn A Davis, Sameer A Sheth, H Isaac Chen, Daniel Yoshor, Michael S Beauchamp

Faculty, Staff and Students Publications

Human speech perception is multisensory, integrating auditory information from the talker's voice with visual information from the talker's face. BOLD fMRI studies have implicated the superior temporal gyrus (STG) in processing auditory speech and the superior temporal sulcus (STS) in integrating auditory and visual speech, but as an indirect hemodynamic measure, fMRI is limited in its ability to track the rapid neural computations underlying speech perception. Using stereoelectroencephalography (sEEG) electrodes, we directly recorded from the STG and STS in 42 epilepsy patients (25F, 17M). Participants identified single words presented in auditory, visual, and audiovisual formats with and without added auditory …

Alterations Of The Upper Respiratory Microbiome Among Children Living With Hiv Infection In Botswana, Sweta M Patel, John Farirai, Mohamed Z Patel, Sifelane Boiditswe, Leabaneng Tawe, Shimane Lekalake, Mogomotsi Matshaba, Andrew P Steenhoff, Tonya Arscott-Mills, Kristen A Feemster, Samir S Shah, Nathan Thielman, Coleen K Cunningham, Lawrence A David, David M Murdoch, Matthew S Kelly

Faculty, Staff and Students Publications

Children living with HIV (CLWH) are at high risk of colonization and infection by respiratory pathogens, though this risk can be reduced by other microbes in the upper respiratory microbiome. The impact of HIV infection on the pediatric upper respiratory microbiome is poorly understood, and we sought to address this knowledge gap by identifying associations between HIV infection and the nasopharyngeal microbiomes of Batswana children. We enrolled Batswana CLWH (< 5 years) and age- and sex-matched HIV-exposed, uninfected and HIV-unexposed, uninfected children in a cross-sectional study. We used shotgun metagenomic sequencing to compare nasopharyngeal microbiomes by HIV status. Among the 143 children in this study, HIV and HIV-associated immunosuppression were associated with alterations in nasopharyngeal microbiome composition, including lower abundances of Corynebacterium species associated with resistance to bacterial pathogen colonization. These findings suggest that the upper respiratory microbiome may contribute to the high risk of respiratory infections among CLWH.

Conversion Of Failed Anatomic Total Shoulder Arthroplasty To Reverse Shoulder Arthroplasty Yields Similar Pain And Functional Outcomes To Primary Reverse Shoulder Arthroplasty But Has A Higher Baseplate Failure Rate: A Matched Cohort Study., Kevin A Hao, Trevor G Simcox, Keegan M Hones, Jonathan O Wright, Thomas W Wright, Tyler Lamonica, Bradley S Schoch, Joseph J King

Faculty, Staff and Student Publications

Background: To investigate whether patients who initially underwent anatomic total shoulder arthroplasty (aTSA) for glenohumeral osteoarthritis and were subsequently revised to reverse TSA (rTSA) due to rotator cuff failure or glenoid loosening ultimately attained a similar clinical outcome compared with those who underwent primary rTSA and identify predictors of poor outcomes in the former population.

Methods: We did a single-center retrospective review of 63 shoulders who underwent revision rTSA after primary aTSA that failed due to glenoid component loosening (n = 32), rotator cuff failure (n = 24), or recurrent instability (n = 7). Pain and functional outcomes at minimum …

Preoperative Brain Mapping Predicts Language Outcomes After Eloquent Tumor Resection, Matthew T Muir, Kyle Noll, Sarah Prinsloo, Hayley Michener, Jeffrey I Traylor, Vinodh A Kumar, Chibawanye I Ene, Sherise Ferguson, Ho-Ling Liu, Jeffrey S Weinberg, Frederick Lang, Brian A Taylor, Stephanie J Forkel, Sujit S Prabhu

Faculty, Staff and Student Publications

When operating on gliomas near critical language regions, surgeons risk either leaving residual tumor or inducing permanent postoperative language deficits (PLDs). Despite the advent of intraoperative mapping techniques, subjective judgments frequently determine important surgical decisions. We aim to inform data-driven surgery by constructing a non-invasive mapping approach that quantitatively predicts the impact of individual surgical decisions on long-term language function. This study included 79 consecutive patients undergoing resection of language-eloquent gliomas. Patients underwent preoperative navigated transcranial magnetic stimulation (TMS) language mapping to identify language-positive sites ("TMS points") and their associated white matter tracts ("TMS tracts") as well as formal language …

Optimal Control In Combination Therapy For Heterogeneous Cell Populations With Drug Synergies., Simon F. Martina-Perez, Samuel W S Johnson, Rebecca M. Crossley, Jennifer C. Kasemeier, Paul M. Kulesa, Ruth E. Baker

Manuscripts, Articles, Book Chapters and Other Papers

Cell heterogeneity plays an important role in patient responses to drug treatments. In many cancers, it is associated with poor treatment outcomes. Many modern drug combination therapies aim to exploit cell heterogeneity, but determining how to optimise responses from heterogeneous cell populations while accounting for multi-drug synergies remains a challenge. In this work, we introduce and analyse a general optimal control framework that can be used to model the treatment response of multiple cell populations that are treated with multiple drugs that mutually interact. In this framework, we model the effect of multiple drugs on the cell populations using a …

A Social Media Campaign And Web-Based Survey About Prostate Cancer Genetics: Mixed Methods Study, Amy Leader, Stacy Loeb, Preethi Selvan, Ashley Hunter, Rebecca Hartman, Scott Keith, Veda Giri

Department of Medical Oncology Faculty Papers

BACKGROUND: Germline genetic variants are important for prostate cancer (PCa) management and hereditary cancer risk assessment, but testing is underused. Furthermore, patients are often unaware of the genetic connections to PCa. Social media is increasingly serving as a source of awareness for health information and a method to gather data from a large population.

OBJECTIVE: There were three objectives: to (1) create and test social media messages related to PCa genetics and genetic testing, (2) determine which social media message was most engaging, and (3) assess knowledge of and attitudes toward PCa genetic testing through an online survey using the …

Organism-Specific Sequence Motifs Link Ribosomal Rnas To Brain Disorders, Isidore Rigoutsos, Stepan Nersisyan, Eric Londin, Iliza Nazeraj, Bonnie Dong, Anastasios Vourekas, Phillipe Loher

Computational Medicine Center Faculty Papers

We report that in humans, mice, fruit flies, and worms, the ribosomal RNAs and the transcribed spacers of 45S are densely packed with organism-specific sequence motifs that are primarily shared with nervous system genes. The human ribosomal RNAs and 45S spacers contain 1,723 such motifs. Specific combinations of these motifs are predominantly found in 3,430 human nervous system genes, of which 1,046 are genes associated with brain disorders, including autism spectrum disorder and schizophrenia. The sequences of the 1,723 motifs and their locations in the introns and exons of nervous system genes are unique to primates. Experimental evidence indicates that …

Inhibition Of Osteosarcoma Lung Metastases By Β-Glucan And Cd40 Agonist Is Mediated By Activation Of Macrophages And Nk Cells, Pradeep Shrestha, Rejeena Shrestha, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Background: Osteosarcoma (OS) lung metastases remain a significant therapeutic challenge. Innate immune activation is a promising therapeutic approach. Innate immune agonists can modulate the tumor immune microenvironment and improve therapeutic response.

Methods: Using an experimental syngeneic OS lung metastasis BALB/c mouse model with K7M3-luc OS cells, we evaluated the antitumor effects of yeast-derived particulate β-glucan in prevention and therapeutic settings. We then assessed whether the CD40 agonist (CD40a) in combination with β-glucan increased therapeutic response in two different immune-competent mouse models of OS lung tumor burden.

Results: In the pretreatment settings, mice treated with β-glucan prior to OS cell infusion …

Dissecting Regulatory Non-Coding Gwas Loci Reveals Fibroblast Causal Genes With Pathophysiological Relevance To Heart Failure, Richard Gill, Junedh M Amrute, Kory J Lavine, Et Al.

2020-Current year OA Pubs

Heart failure is caused in part by cardiac remodeling processes that include the death of cardiac myocytes and their replacement by cardiac fibroblasts. Here, we hypothesize that cardiac fibroblasts may harbor epigenetic contexts in which heart disease-associated non-coding SNPs perturb gene expression relevant to disease. To test this, we utilized male primary cardiac fibroblasts to generate high-resolution Hi-C data and integrate it with functional genomic information to annotate and link putative distal regulatory elements in heart disease-associated loci to gene promoters. We identify several target genes with established roles in cardiac fibrosis and/or heart disease (GJA1, TBC1D32, CXCL12, IL6R, and …

Polychlorinated Biphenyls Alter Estrogen Receptor Β-Mediated Epigenetic Regulation, Promoting Endometriosis, Yuri Park, Nuri Sung, Eunsu Kim, Jaeyeong Jeong, Juhee Sim, Mi Jin Park, John P Lydon, Xiaoming Guan, Sang Jun Han

Faculty, Staff and Students Publications

Endometriosis is a pathological condition characterized by the ectopic growth of endometrial cells, leading to chronic pelvic pain and infertility. Epidemiological studies have associated exposure to dioxin-like polychlorinated biphenyls, particularly PCB126, with an increased risk of endometriosis. However, the underlying mechanisms of this association remain poorly understood. We utilized a surgically induced endometriosis mouse model and human endometrial cell lines to assess the impact of PCB126 on endometriosis progression. Mice were exposed to environmentally relevant doses of PCB126. Endometriotic lesion growth, estrogen receptor signaling, receptor tyrosine kinase activity, and gene expression changes induced by PCB126-mediated elevation of DNA methyltransferase 3A …

Dual Targeting Of Orphan Nuclear Receptors Nr4a1 And Nr4a2 For Nonhormonal Endometriosis Therapy, Wai Ning Tiffany Tsui, Yuri Park, Srijana Upadhyay, Da Mi Kim, Lei Zhang, Gus Wright, Amanuel Hailemariam, Arafat Rahman Oany, Sang Jun Han, Stephen Safe

Faculty, Staff and Students Publications

Previous studies show that orphan nuclear receptor 4A1 (NR4A1) regulates endometriotic cell growth, survival, estrogen receptor β (ERβ), mechanistic target of rapamycin signaling and fibrosis. NR4A2 is also expressed in epithelial and stromal derived endometriotic cells, and in this study the effects of 1,1-bis(3'-indolyl)-(3,5-disubstitutedphenyl)methane (DIM-3,5) dual NR4A1/nuclear receptor 4A2 (NR4A2) ligands and knockdown of NR4A1 and NR4A2 were investigated. The dual NR4A1/2 DIM-3,5 analogs inhibited previously identified proendometriotic pathways and gene products, and they also inhibited TWIST1 and multiple markers associated with epithelial-to-mesenchymal transition (EMT). The results show that both NR4A1 and NR4A2 regulate the same pathways, including endometriotic cell …

Germline Determinants Of Toxicity And Efficacy In Patients With Large B-Cell Lymphoma Treated With Car T-Cell Therapy, Paolo Strati, Amanda Brandt, Anath C Lionel, Jared Henderson, Jason R Westin, Sherry Adkins, Elizabeth J Shpall, Partow Kebriaei, Jeremy Ramdial, Neeraj Saini, Sairah Ahmed, Christopher Flowers, Sattva S Neelapu, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

Background: Recent data have suggested that germline genetic aberrations can affect outcomes in patients with large B-cell lymphoma (LBCL) treated with chimeric antigen receptor T-cell therapy (CART). However, a comprehensive analysis of germline determinants of response and toxicity after CART has not yet been described.

Methods: Genome-wide genotyping was performed in 170 patients with LBCL treated with standard of care axicabtagene ciloleucel. Polygenic risk score instruments for blood cell traits and inflammatory markers were obtained from the PGS Catalog and analyzed using PRSice-2. Exploratory gene-based and genome-wide association study analyses were performed. Genetic ancestry of the patients with LBCL was …

Structural Variation, Selection, And Diversification Of The Npip Gene Family From The Human Pangenome., Philip C. Dishuck, Katherine M. Munson, Alexandra P. Lewis, Max L. Dougherty, Jason G. Underwood, William T. Harvey, Pinghsun Hsieh, Tomi Pastinen, Evan E. Eichler

Manuscripts, Articles, Book Chapters and Other Papers

The NPIP gene family is among the most positively selected gene families in humans/apes and drives independent duplication in primate lineages. These duplications promote genetic instability, leading to recurrent disease-associated microduplication and microdeletion syndromes. Despite its importance, little is known about its function or variation in humans, as short-read sequencing cannot distinguish high-identity duplications. Using long-read assemblies of 169 human haplotypes, we find extreme variation in the content and organization of NPIP loci. We identify fixed and polymorphic paralogs and observe ongoing positive selection. With long-read RNA sequencing (RNA-seq), we create paralog-specific gene models, the majority of which were not …

Quiescent Oxphos-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend On Bcl-Xl For Survival, Slawomir Andrzejewski, Marie Winter, Leandro Encarnacao Garcia, Olusiji Akinrinmade, Francisco Madeira Marques, Emmanouil Zacharioudakis, Anna Skwarska, Julio Aguirre-Ghiso, Marina Konopleva, Guangrong Zheng, Susan A Fineberg, Daohong Zhou, Evripidis Gavathiotis, Tao Wang, Eugen Dhimolea

Faculty, Staff and Student Publications

The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, …

Functional Diversity In Gii.4 Norovirus Entry: Hbga Binding And Capsid Clustering Dynamics, B Vijayalakshmi Ayyar, Carmen V Apostol, Janam Jitendra Dave, Soni Kaundal, Joseph A Kendra, Frederick H Neill, Khalil Ettayebi, Sarah Maher, Ramakrishnan Anish, Gabriel I Parra, Göran Larson, Robert L Atmar, Sue E Crawford, B V Venkataram Prasad, Mary K Estes

Faculty, Staff and Students Publications

Human noroviruses (HuNoVs), especially GII.4 strains, are the leading cause of acute viral gastroenteritis worldwide, yet no approved vaccines or antivirals exist. The pandemic GII.4 Sydney 2012 strain enters cells via membrane wounding and clathrin-independent carrier-mediated endocytosis, but it is unclear whether this entry mechanism is conserved across GII.4 variants. We compared early binding and entry of multiple GII.4 variants using wild-type and mutant GII.4 virus-like particles (VLPs) and modified human intestinal enteroid cultures. Only a subset of GII.4 variants, including GII.4 Sydney, form distinct, histo-blood group antigen (HBGA)-dependent capsid clusters on the cell surface. Clustering strains display significantly enhanced …

Implementation Mapping To Identify Best Practices For Implementing Population-Wide Genomic Screening Programs: Protocol For The Focus (Facilitating The Implementation Of Population-Wide Genomic Screening) Study, Megan Roberts, Jarrod Marable, Kimberly Foss, Cason Whitcomb, Deborah Cragun, Adam Buchanan, Miranda Hallquist, Nathaniel Baker, Rebecca Bosch, Derek W Craig, Ingrid Wagner, Maria Fernandez, Chanita Hughes-Halbert, Caitlin Allen

Faculty, Staff and Student Publications

Background: Population-wide genomic screening (PGS) for genetic conditions such as hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia presents opportunities to reduce morbidity and mortality among the 1%-2% of the population at elevated risk for these serious, preventable diseases. With decreasing sequencing costs and growing support from national bodies, there are increasing numbers of PGS programs in the United States. However, guidelines and strategies to support implementation are limited, especially regarding equitable access to PGS. Contextual factors, such as organizational structures and processes, impact PGS implementation, often failing to benefit underrepresented populations. To address these challenges, we …

Estimated Waste Generation From 1 Million Basic Metabolic Panels: A Multisite U.S. Study, Seema Khattri Bhandari, Kwaku Twum, Erving T Laryea, Yaqing Du, Raeshun T Glover, Rachel G Brackbill, William Butler, Khushbu Patel, Christopher W Farnsworth, Christina C Pierre, Steven W Cotten, Joesph R Wiencek

2020-Current year OA Pubs

OBJECTIVES: Clinical laboratory operations consume large amounts of electricity and water and generate considerable quantities of solid waste. In this study, we quantified and compared the estimated solid waste produced from performing one million basic metabolic panels (BMPs) across five major high-throughput chemistry analyzer systems commonly used in the United States. Additionally, we estimated the carbon emissions associated with the electricity and water usage of each analyzer to better understand their environmental impact.

METHODS: Five academic medical centers each using a different clinical chemistry analyzer system, collected their respective annual vendor purchase data (January 2022-December 2022). Consumables including reagent cartridges, …

Assessing A Community Health Worker-Facilitated, Digitally Delivered, Family-Centered Diabetes Management Program: Single-Arm Quasi-Experimental Study, Zenong Yin, Vanessa L Errisuriz, Heather Cuevas, Bertha E Flores, Laura Delfausse, Christina Galvan, Jing Wang, Chengdong Li, Renata Morfin, Shiyu Li, Maysa Sapargeldiyeva, Giliane Yza Muyna, Minyu Zhang, Vanessa Sweet, Deborah Parra-Medina

Faculty, Staff and Student Publications

Background: The high prevalence of type 2 diabetes (T2D) and associated complications disproportionately affect low-income Latino populations, who also experience disparities in diabetes self-management (DSM), including poor medication adherence, physical activity, diet, and glycemic control.

Objective: This study examined, through an academic-community partnership, the effectiveness of ¡Salud, Salud! (an evidence-based, family-centered diabetes self-management education and support [DSMES] program) on primary (glycemic control and quality of life) and secondary (social, psychological, and behavioral factors related to T2D management) outcomes among low-income Latino adults with T2D or prediabetes.

Methods: In total, 81 adults (mean age 48.90 years, SD 12.57; n=57, 70.4%, female; …

Apoe-Calypse Tau: Apoe-Tau Synergy In Alzheimer's Disease, Matthew Paul Lennol, Chiara Bordier, Léana Kamelher, Jason D Ulrich, David M Holtzman, Maud Gratuze

2020-Current year OA Pubs

Alzheimer's disease (AD), the most common cause of dementia, is characterized by the accumulation of amyloid-β (Aβ) in senile plaques and abnormally hyperphosphorylated tau proteins in neurofibrillary tangles. While much of the research has focused on Aβ, tau-mediated neurodegeneration is more closely associated with synaptic loss and cognitive decline in AD, emphasizing the need for a deeper understanding of tau pathology. In this context, the interaction between tau and APOE, particularly the main genetic risk factor for AD APOE ε4, remains underexplored. APOE encodes apolipoprotein E (apoE), a protein important in lipid metabolism. In addition to promoting Aβ deposition, emerging …

Risk Markers For Sudden Unexpected Death In Epilepsy: An Observational, Prospective, Multicentre Cohort Study, Manuela Ochoa-Urrea, Xi Luo, Laura Vilella, Nuria Lacuey, Shirin Jamal Omidi, Norma J Hupp, Blanca Talavera, Johnson P Hampson, M R Sandhya Rani, Shiqiang Tao, Xiaojin Li, Christina Y Miyake, Licong Cui, Jaison S Hampson, Ganne Chaitanya, Yash Shashank Vakilna, Rup K Sainju, Daniel Friedman, Maromi Nei, Luke Allen, Catherine A Scott, Joana Oliveira, Brian Gehlbach, Stephan U Schuele, Jennifer A Ogren, Ronald M Harper, Beate Diehl, Lisa M Bateman, George B Richerson, Jose-Miguel Yamal, Guo-Qiang Zhang, Orrin Devinsky, Samden D Lhatoo

Faculty, Staff and Student Publications

Background: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Generalised-particularly nocturnal-convulsive seizures, longstanding epilepsy, and solitary living have been identified retrospectively as risk factors. No definitive electroclinical biomarkers have been prospectively ascertained. This study aimed to identify SUDEP risk markers using multimodality data with long-term follow-up.

Methods: This prospective, multicentre, observational cohort study, conducted at nine centres (eight in the USA and one in the UK), recruited children and adults with epilepsy who were undergoing prolonged video-electroencephalographic (EEG) monitoring. Inclusion criteria were diagnosis of epilepsy by an epilepsy specialist, with or without drug resistance; age …

Male Hypogonadism: Recommendations From The Fifth International Consultation On Sexual Medicine (Icsm 2024), Mohit Khera, Luiz Otavio Torres, Ethan D Grober, Abraham Morgentaler, Martin Miner, Thomas Hugh Jones, Jesse N Mills, Andrea Salonia

Faculty, Staff and Students Publications

Introduction: Male hypogonadism is a clinical condition combining low circulating testosterone (T) and specific signs and symptoms associated with impaired hormone production.

Objectives: To provide the 5th International Consultation for Sexual Medicine consensus paper with recommendations concerning management strategies for hypogonadism.

Outcomes: A narrative review combined with expert opinions on major topics concerning diagnosis of male hypogonadism; treatment options; T impact toward cardiovascular, metabolic, sexual, and reproductive health; and prostate cancer (PCa).

Methods: A consensus panel was held with leading Sexual Medicine experts during the 5th ICSM. Relevant English-language peer-reviewed literature was reviewed with a focus on research from but …

Oncopacket: Integration Of Cancer Research Data Using Ga4gh Phenopackets., Michael Sierk, Daniel Danis, Sujay Patil, Nobal Kishor, Rajdeep Mondal, Abhishek Jha, Qingrong Chen, Chunhua Yan, Monica Munoz-Torres, Daoud Meerzaman, Peter N Robinson, Justin T Reese

Faculty Research 2025

SUMMARY: Lack of data integration remains a significant impediment to cancer research, and many analyses still require customized software to transform and prepare cancer data. We describe a software package to harmonize genetic and clinical cancer data into the GA4GH Phenopacket schema, an ISO standard for representing clinical case data. We integrated demographic, mutation, morphology, diagnosis, intervention, and survival data using case data from the National Cancer Institute for 12 cancer types. The Phenopacket standard provides a foundation for downstream use, including sophisticated statistical and AI/ML analyses. We demonstrate fitness for purpose by using the integrated data to recapitulate a …

Automating Candidate Gene Prioritization With Large Language Models: From Naive Scoring To Literature-Grounded Validation., Taushif Khan, Mohammed Toufiq, Marina Yurieva, Nitaya Indrawattana, Akanitt Jittmittraphap, Nathamon Kosoltanapiwat, Pornpan Pumirat, Passanesh Sukphopetch, Muthita Vanaporn, Karolina Palucka, Basirudeen Syed Ahamed Kabeer, Darawan Rinchai, Damien Chaussabel

Faculty Research 2025

MOTIVATION: Identifying promising therapeutic targets from thousands of genes in transcriptomic studies remains a major bottleneck in biomedical research. While large language models (LLMs) show potential for gene prioritization, they suffer from hallucination and lack systematic validation against expert knowledge.

RESULTS: The framework identified 609 sepsis-relevant genes with >94% filtering efficiency, demonstrating strong enrichment for inflammatory pathways including TNF-α signaling, complement activation, and interferon responses. Literature validation yielded 30 ultra-high confidence therapeutic candidates, including both established sepsis genes (IL10, TREM1, S100A9, NLRP3) and novel targets warranting investigation. Benchmark validation against expert-curated databases achieved 71.2% recall, with systematic correlation between computational …

A Needed Nomenclature For Nucleosomes, Michael-Christopher Keogh, Genevieve Almouzni, Andrew J Andrews, Karim-Jean Armache, Cheryl H Arrowsmith, Sung Hee Baek, Mark T Bedford, Emily Bernstein, Jacques Côté, Yael David, John M Denu, Beat Fierz, Benjamin A Garcia, Karen C Glass, Or Gozani, Kristian Helin, Steven Henikoff, Ole N Jensen, Steven Z Josefowicz, Neil L Kelleher, Tatiana G Kutateladze, Herbert H Lindner, Chao Lu, Karolin Luger, Parag Mallick, Catherine A Musselman, Tom W Muir, Ljiljana Paša-Tolić, Robert Schneider, Xiaobing Shi, Yang Shi, Simone Sidoli, Lloyd M Smith, Jessica K Tyler, Cynthia Wolberger, Jerry L Workman, Brian D Strahl, Nicolas L Young

Faculty, Staff and Student Publications

Histone post-translational modifications (PTMs) are crucial to eukaryotic genome regulation, with a range of reported functions and mechanisms of action. Though often studied individually, it has long been recognized that the modifications function by combinatorial synergy or antagonism. Interplay may involve PTMs on the same histone, within the same nucleosome (containing a histone octamer), or between nucleosomes in higher-order chromatin. Given this, the field must distinguish ever greater complexity, and the context in which it is studied, with brevity and precision. The proteoform was introduced to define individual forms of a protein by sequence and PTMs, followed by the nucleoform …

Genome-Wide Analysis Of Dna Methylation Signatures Linking Prenatal Exposure To The Chinese Great Famine And Blood Lipids In Late Adulthood: The Genomic Research Of The Chinese Famine (Grecf) Study, Huan Wang, Luqi Shen, Tingting Liu, Ruiyuan Zhang, Zhenghe Wang, Jingkai Wei, Ye Shen, Jinzhen Guo, Toni Miles, Changwei Li, Zhiyong Zou

Faculty, Staff and Student Publications

Background/objectives: Prenatal exposure to famine can lead to lasting health effects through changes in DNA methylation. This study aims to evaluate the impact of prenatal exposure to the Chinses Great Famine (1959-1961) on human epigenome and the subsequent influence on blood lipids.

Methods: We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and prenatal exposure to the Chinese Great Famine as well as blood lipids among eight participants exposed to famine and eight sex-matched participants (born ≤ 3 years after the famine). Genome-wide DNA methylation sites were profiled using the Illumina EPIC BeadChip, which covers 850K methylation …

The 10-Year Functional Outcome Of Ponseti Treatment Of Idiopathic And Arthrogrypotic Clubfeet With An Age-Matched Control, Chris Church, Nicole Wang, Stephanie Butler, Jose J Salazar-Torres, John Henley, Freeman Miller, Nancy Carlin, Maureen Donohoe, L Reid Nichols

Faculty and Staff Publications

Background: The Ponseti method is accepted as an effective primary conservative treatment for idiopathic clubfoot (IC) using serial casting, percutaneous Achilles tenotomy, and prolonged bracing. The outcomes of its use in treating rigid clubfoot in arthrogryposis are unclear. This study assesses the outcomes of the Ponseti method in children with IC and arthrogrypotic clubfoot at an average age of 10 years.

Methods: Outcomes of the Ponseti method were retrospectively studied in ambulatory children ages 8.0 to 12.9 years in the gait lab between 2004 and 2024. Children were excluded due to the presence of nonidiopathic or nonarthrogryposis-related clubfoot and history …

International Headache Society Evidence-Based Guidelines On The Use Of Non-Invasive Neuromodulation Devices For The Acute And Preventive Treatment Of Migraine, Hsiangkuo Yuan, Serena L. Orr, Mohammad A. M. Al-Karagholi, Messoud Ashina, Fred Cohen, Hans-Christoph Diener, David W. Dodick, Rigmor Højland Jensen, Michael J. Marmura, Daniele Martinelli, Manjit S. Matharu, Anja S. Petersen, Patricia Pozo-Rosich, Simona Sacco, Lucy Simmonds, Cristina Tassorelli, Stewart J. Tepper, Gisela M. Terwindt, Shuu-Jiun Wang, Jiunn-Tyng Yeh, Stephen D. Silberstein

Department of Jefferson Headache Center Papers and Presentations

ObjectiveTo develop evidence-based clinical practice guidelines for non-invasive neuromodulation devices in acute and preventive migraine treatment.MethodsA systematic review was conducted across six databases from 1946 to April 2025. Randomized controlled trials evaluating Food and Drug Administration-cleared or Conformité Européenne (CE)-marked non-invasive neuromodulation devices were included. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, and recommendations were developed through consensus following GRADE Evidence-to-Decision frameworks. The working group comprised 15 senior members and six junior members.ResultsFrom 1536 initial records, 15 studies met the inclusion criteria and were finally used to develop evidence-based recommendations. …

Evaluation Of Hippocampal Dlgap2 Overexpression On Cognition, Synaptic Function, And Dendritic Spine Structure In A Translationally Relevant Ad Mouse Model., Andrew R Ouellette, Kristen M S O'Connell, Catherine Kaczorowski

Faculty Research 2025

INTRODUCTION: Developing effective therapeutics for Alzheimer's disease (AD) requires a better understanding of the molecular drivers of the disease. Our previous work nominated DLGAP2 as a modifier of age-related cognitive decline and risk for AD. We tested the hypothesis that overexpression of DLGAP2 in the hippocampus would protect against cognitive and synaptic deficits in a susceptible F1 5XFAD model.

METHODS: DLGAP2 was overexpressed in the hippocampus of F1 hybrid 5XFAD and non-transgenic littermates using a viral approach. Cognitive function, electrophysiological properties, and dendritic spine morphology were assessed at 6 and 14 months of age.

RESULTS: DLGAP2 overexpression impaired synaptic plasticity …

Genetic And Epigenetic Screens In Primary Human T Cells Link Candidate Causal Autoimmune Variants To T Cell Networks., Ching-Huang Ho, Maxwell A Dippel, Meghan S Mcquade, Leann P Nguyen, Arpit Mishra, Stephan Pribitzer, Samantha Hardy, Harshpreet Chandok, Florence M Chardon, Troy A Mcdiarmid, Hannah A Deberg, Jane H Buckner, Jay Shendure, Carl G De Boer, Michael H Guo, Ryan Tewhey, John P Ray

Faculty Research 2025

Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4⁺ T cells, suggesting that they could alter disease risk through changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here we tested >18,000 autoimmune disease-associated variants for allele-specific effects on expression using massively parallel reporter assays in primary human CD4⁺ T cells. We find 545 variants that modulate expression in an allele-specific manner (emVars). Primary T cell emVars greatly enrich for likely causal variants, are mediated by common upstream pathways and …